1-156134499-C-G

Variant names:

• chr1-156134499-C-G
• rs1553265177
• NM_170707.4:c.610C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_170707.4(LMNA):​c.610C>G​(p.Leu204Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L204M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: LMNA NM_170707.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 7.86

Genes affected

LMNA (HGNC:6636): (lamin A/C) The protein encoded by this gene is part of the nuclear lamina, a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Alternative splicing results in multiple transcript variants. Mutations in this gene lead to several diseases: Emery-Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot-Marie-Tooth disease, and Hutchinson-Gilford progeria syndrome. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_170707.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156134500-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520416.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the LMNA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 178 curated pathogenic missense variants (we use a threshold of 10). The gene has 69 curated benign missense variants. Gene score misZ: 2.3673 (below the threshold of 3.09). Trascript score misZ: 3.0905 (above the threshold of 3.09). GenCC associations: The gene is linked to familial partial lipodystrophy, Dunnigan type, autosomal recessive Emery-Dreifuss muscular dystrophy, LMNA-related cardiocutaneous progeria syndrome, atrioventricular block, dilated cardiomyopathy 1A, Emery-Dreifuss muscular dystrophy 2, autosomal dominant, atypical Werner syndrome, restrictive dermopathy 1, autosomal semi-dominant severe lipodystrophic laminopathy, Emery-Dreifuss muscular dystrophy 3, autosomal recessive, dilated cardiomyopathy, Charcot-Marie-Tooth disease type 2B1, dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome, arrhythmogenic right ventricular cardiomyopathy, familial isolated dilated cardiomyopathy, mandibuloacral dysplasia with type A lipodystrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, heart-hand syndrome, Slovenian type, congenital muscular dystrophy due to LMNA mutation, lethal restrictive dermopathy, Hutchinson-Gilford progeria syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LMNA	NM_170707.4	c.610C>G	p.Leu204Val	missense_variant	Exon 3 of 12	ENST00000368300.9	NP_733821.1
LMNA	NM_005572.4	c.610C>G	p.Leu204Val	missense_variant	Exon 3 of 10	ENST00000677389.1	NP_005563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LMNA	ENST00000368300.9	c.610C>G	p.Leu204Val	missense_variant	Exon 3 of 12	1	NM_170707.4	ENSP00000357283.4
LMNA	ENST00000677389.1	c.610C>G	p.Leu204Val	missense_variant	Exon 3 of 10		NM_005572.4	ENSP00000503633.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461838 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Uncertain:2

Jul 25, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with valine at codon 204 of the LMNA protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Aug 09, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2 Uncertain:1

Mar 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 204 of the LMNA protein (p.Leu204Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of LMNA-related disease (PMID: 27884249; Invitae). ClinVar contains an entry for this variant (Variation ID: 519420). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMNA protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Aug 19, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hutchinson-Gilford syndrome;C0410190:Emery-Dreifuss muscular dystrophy 2, autosomal dominant;C0796031:Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome;C1449563:Dilated cardiomyopathy 1A;C1720860:Familial partial lipodystrophy, Dunnigan type;C1854154:Charcot-Marie-Tooth disease type 2B1;C1857829:Heart-hand syndrome, Slovenian type;C2750035:Emery-Dreifuss muscular dystrophy 3, autosomal recessive;C2750785:Congenital muscular dystrophy due to LMNA mutation;C5399785:Mandibuloacral dysplasia with type A lipodystrophy;C5676942:Restrictive dermopathy 2 Uncertain:1

May 27, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Uncertain:1

Mar 20, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L204V variant (also known as c.610C>G), located in coding exon 3 of the LMNA gene, results from a C to G substitution at nucleotide position 610. The leucine at codon 204 is replaced by valine, an amino acid with highly similar properties, and is located in the coil 1b domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
CardioboostCm	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;.;.;D;.;.;.;D;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.8	M;.;M;M;M;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.3	N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.82
Sift	Benign	0.051	T;T;D;D;D;D;D;D;D
Sift4G	Benign	0.078	T;T;T;T;T;T;T;D;T
Polyphen		0.91	P;.;P;P;.;.;D;.;.
Vest4		0.82
MutPred		0.69		Gain of methylation at K208 (P = 0.0835);Gain of methylation at K208 (P = 0.0835);Gain of methylation at K208 (P = 0.0835);Gain of methylation at K208 (P = 0.0835);Gain of methylation at K208 (P = 0.0835);.;.;.;.;
MVP		0.96
MPC		2.0
ClinPred		0.94	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553265177; hg19: chr1-156104290;